Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia.

Abstract

Deficits in working memory, a core disturbance of schizophrenia, appear to emerge from an impaired capacity to generate gamma oscillations in the neural networks of the prefrontal cortex. Cortical gamma oscillations arise principally in layer 3 where strong inhibitory inputs from the parvalbumin (PV) basket cell class of GABA neurons synchronize the activity of local groups of pyramidal neurons which in turn send excitatory inputs to PV basket cells. Schizophrenia is associated with deficits in markers of excitatory activity of layer 3 pyramidal cells and multiple pre- and postsynaptic abnormalities consistent with weaker inhibitory inputs to pyramidal cells from PV basket cells. These findings suggest that prefrontal cortical dysfunction in schizophrenia results from an “upstream” deficit in pyramidal cell excitation and that inhibition from PV basket cells is downregulated to compensate for this low network activity. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power in prefrontal neural networks required for optimal working memory performance.